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As Medical Cannabis Moves Mainstream, Can It Provide Pain Relief?

Marijuana. Pot. Weed. Dope, grass, reefer. Blunts, dabs and shatter. The list of names for the drug derived from the cannabis plant is long—and growing. For many people, the words conjure images of Cheech and Chong movies, hippies at Woodstock, or Dennis Hopper on his motorcycle in Easy Rider. But cannabis use has evolved over the past 50 years. While plenty of people still use the psychoactive substance recreationally, others are finding it brings them relief from chronic pain and other conditions. Yet scientists still have little grasp of how cannabis can best be used to fight pain. “We are at an interesting time in history where we have science and popular culture coming together in a unique way,” said Mark Ware, a pain researcher and clinician at McGill University, Montreal, Canada, speaking in May in Palm Springs, California, US, at the 2015 annual meeting of the American Pain Society (APS), a professional society of researchers and clinicians dedicated to improving research, public policy and clinical treatment of pain.

Cannabis now represents a multibillion-dollar industry—the fastest growing in the US. Although the substance remains illegal under US Federal law, cannabis use is on the rise: a 2013 report found that nearly 20 million Americans over age 12—or 7.5% of the population—had used it in the past month. Twenty-three US states, the District of Columbia, and Canada have legalized marijuana use in some form. But does cannabis help patients with chronic pain? Driven by reports of success stories from patients, researchers are trying to determine whether the drug relieves chronic pain and how. Although much research remains to be done, human and animal studies do hint at potential benefits of cannabis-derived drugs for pain.

History of cannabis
Cannabis has been around for millions of years, and historical writings indicate it has been used as a therapeutic for pain for over four thousand years, in China, India, the Middle East, and ancient Greece and Rome. Interestingly, there is some evidence that William Shakespeare might have regularly smoked marijuana, and English medical texts of the 1600s described its benefits for pain and depression. Early Americans, including George Washington and Thomas Jefferson, grew hemp—also derived from the Cannabis sativa plant—primarily for its use as a fiber. In 1839, British physician William O’Shaughnessy published his observations of the clinical use of cannabis in India, bringing it into the modern British pharmacopeia. Cannabis tinctures were routinely used during the Victorian period in Britain and America, but it was widely banned in the US along with alcohol and other drugs during the Prohibition era of the 1910s. By the 1930s, its medicinal use declined in the face of new analgesic drugs such as aspirin and opioids, and it was removed from the US pharmacopeia in 1942, officially ending its medicinal use there. In 1970, the US government passed the Controlled Substances Act, which classified cannabis, along with heroine and cocaine, as a “Schedule I” drug—one with potential for abuse and no medical benefits.

The most common way to use marijuana is to smoke the “buds,” or flowers, from the Cannabis sativa plant. Cannabinoids, the active ingredients, can also be isolated from the plant or synthetically produced. Understandably, many patients and doctors are wary of a pain drug that must be smoked, but alternative delivery methods are increasingly available, including edibles and tinctures containing cannabinoids. Vaporization, in which oil containing cannabinoids is heated but not burned, also delivers the drug effectively.

While the US Food and Drug Administration (FDA) has not approved any use of the cannabis plant for medical purposes, several cannabinoid drugs are approved by the FDA, including dronabinol and nabilone, which enhance appetite in cancer patients undergoing chemotherapy and people with acquired immune deficiency syndrome (AIDS). Another drug, nabiximols, has been approved in 27 countries (but not the US) for spasticity in patients with multiple sclerosis, and clinical trials are underway in the US studying nabiximols for cancer pain.

Does it work?
“Much of what we know about the effectiveness of cannabis is derived from patients themselves,” Ware told RELIEF in an interview. Researchers are studying cannabis, Ware said, not because pharmaceutical companies and corporate interests developed the drug; rather it has been a patient-led movement. “And the studies I’ve been involved in and other clinical trials have supported the claims those patients have made,” especially for neuropathic pain, the type that arises from damage to the nervous system, said Ware, who is also executive director of the non-profit Canadian Consortium for the Investigation of Cannabinoids. In studies using animal models of pain, the evidence is overwhelming: cannabinoids improved symptoms in every type of pain model tested. In humans, the evidence is more limited, in large part because cannabis is still strictly regulated as a Schedule I substance, significantly impeding research in people.

Although an individual study may or may not show efficacy—or positive effects—of cannabis for reducing pain, the size, duration and design of each study must be considered when assessing them. Researchers conduct meta-analyses, studies that analyze many clinical trials by taking these factors into account, to determine a drug’s efficacy. A recent meta-analysis by Ware and colleagues showed that, although the studies that have been completed are small and short, “they suggest that cannabinoids are safe, demonstrate a modest analgesic [pain-relieving] effect, and provide a reasonable treatment option for chronic pain,” Ware said at the APS meeting.

But not all meta-analysis studies have had positive results. Andrew Rice, a professor of pain research at Imperial College, London, UK, served as part of a committee formed by the Neuropathic Pain Special Interest Group within the International Association for the Study of Pain (IASP)—another professional society dedicated to pain research, policy and treatment—that set out to analyze clinical trials of cannabis (along with all other available pharmacological treatments) specifically for neuropathic pain. That analysis, he told RELIEF, showed little evidence of efficacy for cannabis. “The trials that do suggest efficacy are too short or low quality to show it, and the high-quality studies do not show efficacy,” Rice said. The discrepancy between the meta-analyses probably lies in which studies were included in each one.

Is it safe?
The question of long-term safety also remains murky, because clinical studies in humans involve small numbers of people and do not last long enough to detect long-term health risks. However, marijuana has long been the most commonly used illicit drug in the US, and it clearly carries much lower risks compared to narcotics. For example, death by overdose of marijuana is unheard of. A recent year-long study led by Ware compared chronic pain patients taking cannabis to those using other drugs for pain but not cannabis. The researchers found that minor side effects such as nausea or dizziness were more common among cannabis users than non-users, but severe adverse effects were rare and similar between the groups. “It appears the drug is reasonably well tolerated—especially when compared to other drugs that patients are taking for pain,” Ware told RELIEF.

What researchers do know about the long-term risks of marijuana smoking comes mainly from epidemiological studies that followed large groups of people who began using marijuana early in life. Researchers agree that the risks are higher for younger users. The brain’s own natural cannabinoid signaling system plays an important role in brain development, which continues into adulthood and may be disrupted by marijuana use at an early age or in pregnant mothers. As marijuana use becomes more socially accepted, Ware said at APS, “we don’t want to let this message spill over to kids and let them think it’s OK for them. If you can get to age 18 or even 25 before using, it’s much safer.”

According to a report authored by Nora Volkow, director of the National Institute on Drug Abuse (NIDA), part of the National Institutes of Health (NIH), one of the greatest risks associated with long-term marijuana use is addiction: about one in nine adults who uses marijuana becomes addicted, and that figure increases for those who smoke beginning in adolescence or very heavily. Pot has a reputation as a “gateway drug”—one that increases the likelihood of using harder drugs—but research shows that the same can be said of alcohol and cigarettes. The short-term effects of using marijuana include altered cognition, which could impair the ability to learn, make decisions or operate a car, and long-term effects on cognition have also been seen in those who continuously smoked pot from adolescence into adulthood. Some studies show that marijuana increases the risk of traffic accidents, but not as much as alcohol does. Surprisingly, a study showed that marijuana did not increase risk of lung and throat cancers once the researchers accounted for cigarette smoking.

Perhaps most worrisome is an association in adolescent users between marijuana use and mental illnesses, including depression, anxiety and schizophrenia. However, many of the factors associated with marijuana use, including early life stress or trauma, also increase risk for psychosis, so a clear role has not been established for marijuana in causing mental illness. “The truth is that this [severe side effect] probably occurs, like most rare side effects, in a very small number people, but we don’t know who will or who won’t be affected,” said Rice. But researchers are discovering clues to who might be affected: multiple studies have now shown that a genetic variation influences the risk for psychosis in adolescents, and that risk was significantly increased with marijuana use. People with a history or high risk of mental illness should not use cannabis, Ware said.

Cannabinoids in the nervous system
The active ingredients in the Cannabis sativa plant, called cannabinoids, are found only on tiny hairs that cover the flowers—not the leaves or stems—of female plants. Over 80 cannabinoids have been identified, but the two most abundant and best understood by researchers are called delta-9-tetrahydrocannabinol, or THC, and cannabidiol, or CBD. Both cannabinoids appear to have some health benefits, but THC is responsible for the drug’s psychoactive effects, whereas CBD does not produce a high or the cognitive impairment associated with marijuana. The brain naturally produces similar molecules called endogenous cannabinoids, which are involved in regulating pain, appetite, mood and memory. (Some other plant-derived drugs, including opioids like morphine, also work through endogenous signaling systems). Both endogenous and cannabis-derived cannabinoids activate specialized molecules called receptors found on the surface of cells. For example, THC activates a receptor called CB1, found on neurons in the brain, and CB2, associated with immune cells.

Researchers have found that THC acting at CB1 receptors affects neuronal communication, which likely accounts for its psychoactive effects. The place where neurons communicate with one another is called a synapse. A “talking” neuron releases chemical signaling molecules called neurotransmitters, which travel across the synapse to receptors on the “listening” neuron. There, the neurotransmitters trigger a bioelectrical signal that gets passed on to other neurons.

But cannabinoids are signaling molecules that work slightly different from neurotransmitters. Whereas neurotransmitters are packaged in tiny vesicles inside cells, oil-based cannabinoids are made in and released directly from the cell membrane of the listening neuron, and they travel back to the talking neuron, where they bind their receptors. Cannabinoids then prevent the release of neurotransmitters from the talking neuron, dampening neural signaling. The effects can vary greatly, depending on the type of neurons involved and where they are found in the brain. “When patients take cannabinoids, they put the brakes on abnormal nerve firing,” Ware said at APS. Researchers believe this dampening effect might give rise to the benefits of cannabis for symptoms including chronic pain, anxiety, spasticity and seizures.

“The shortcomings of CB1 as a target for pain treatment are the psychoactive effects associated with that particular receptor,” said Michael Oshinsky, program director for pain and migraine at the National Institute of Neurological Disorders and Stroke (NINDS), part of NIH. In contrast to the neuronal CB1 receptors, activation of CB2 receptors does not seem to produce those side effects, so drugs aimed specifically at CB2 might avoid them. For that reason, Oshinsky said, “recently there’s been a push in research to understand the CB2 receptor, which is well known to be expressed in immune cells outside the CNS [central nervous system]. But it is also found on microglia, the immune cells of the CNS, which are involved in pain modulation and inflammatory reactions inside the brain.” Its association with immune cells might suggest a role for CB2 in regulating inflammatory pain conditions. Oshinsky emphasized that NIH-funded researchers are not excluding CB1 as a significant drug target, but that activating CB1 can have significant negative side effects. “Whenever you’re developing a compound to take advantage of an endogenous system, you want to balance side effects with treatment effects,” he said.

One way to potentially minimize side effects might be to find ways to tap into the brain’s own endogenous cannabinoid system. “The brain has mechanisms for making more endogenous cannabinoids, which the body and brain use to modulate pain as well as other pathological conditions,” Oshinsky said. “If we can understand how the brain turns up production, perhaps we can have the brain use its own ligand [the molecule that activates the receptor], and we can just change the amount that’s available.” He explained that other drug targets might be the molecules responsible for degradation, shuttling, production or release of endogenous cannabinoids, all of which affect the compounds’ abundance. Understanding the basic science of those processes, Oshinsky said, will be key, and are a major effort of NIH-sponsored research. ”That’s where the true discoveries are going to come from—then we can bring in the chemists and design synthetic molecules to take advantage of the endogenous system that we have worked hard to understand at a basic science level.” Oshinsky added that while “thousands of people may be using cannabinoids where they are legal or available, that doesn’t mean it works. Through research of the endogenous system, we can have an informed discussion about the appropriate role for the use of cannabinoids or other molecules to modulate that system.”

Unlike THC, CBD—the other major known active substance in cannabis—does not bind strongly to the CB1 or CB2 receptors; it seems to affect other signaling systems in the brain, but researchers do not yet understand how. Because CBD provides some benefits without psychoactive effects, researchers believe CBD-based drugs may have wider potential than those containing THC. For example, a drug called Epidiolex is now in clinical trials for rare, severe forms of epilepsy, and meanwhile is being prescribed to some children under the FDA’s Compassionate Use program. “The NIH recognizes the need for additional research on the therapeutic effects of CBD and other cannabinoids, and supports ongoing efforts to reduce barriers to research in this area,” Volkow said in her testimony to the US Senate Caucus on International Narcotics Control in June 2015.

Those barriers also extend to animal research, according to Rebecca Craft, a pain researcher who has long studied cannabinoids at Washington State University, Pullman, US. “It has become more difficult to get a Schedule I license—it takes longer,” said Craft, who has held the license issued to researchers by the US Drug Enforcement Agency (DEA) since 1999. In Washington, where all marijuana use was recently legalized, tax revenue from its sale has been made available to researchers at the University of Washington and Washington State University, but research proposals may go unfunded because researchers who applied for new licenses months ago have yet to receive them, Craft told RELIEF. In addition, each drug compound to be studied must be individually licensed, Craft said, “even the ones that have no known abuse potential, like cannabidiol.”

Drug problems
Considering the epidemic of opioid abuse in the US—nearly two million people suffer from prescription pain medication abuse, and another half million are addicted to heroin—cannabinoids may provide a safer alternative. Studies in animals suggest that cannabinoids might work synergistically with opioid drugs, which would allow patients to use lower doses of both. While the long-term risks of cannabis use are not fully understood, they are certainly lower than opioid drug use, which unlike cannabis carries an immediate risk of death by overdose. A recent study suggested that cannabis use could lower the number of opioid overdose deaths: in states with legalized medical marijuana, the risk of overdose by prescription opioid medications is about 25% less compared to states where cannabis is illegal—a much greater effect than any other factor, including state monitoring of drug prescriptions.

So should people be using cannabis as a pain therapeutic? “From what we know, cannabis appears to be a safe drug, but it’s a powerful drug, and it should be used with caution and respect,” Ware told RELIEF. It should be used in the context of medical management of pain, he went on to say, as part of a multifaceted strategy including not just pharmacotherapy, but also physical activity, psychosocial support, and so on. “It needs to be part of a pain management strategy, but not be the pain management strategy.” And, Ware said, it needs to be undertaken with the awareness and support of health care providers, and not in some secret way. Used appropriately, Ware concluded, cannabis may help with goals like reducing use of opioids, increasing physical activity and improving functional levels in patients with chronic pain.

Stephani Sutherland, PhD, is a neuroscientist, yogi, and freelance journalist in Southern California. Find her at StephaniSutherland.com or on Twitter @SutherlandPhD

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